PROJECTSUMMARY Schizophrenia is a heritable psychiatric disease affecting approximately 1% of the population. The disease is associated with high morbidity and mortality and is a leading cause of disability. Genomewide association studies (GWAS) have identified >100 genetic loci associated with schizophrenia. However standard GWAS are largely limited to detecting simple point mutations, or single nucleotide polymorphisms (SNPs),consistingofsinglebasepairsubstitutions.Thus,GWASisunabletocapturecomplexvariantssuch ascopynumbervariants(CNVs)andtandemrepeats(TRs)thatarenotwelltaggedbySNPs. MultiplelinesofevidencesupportthehypothesisthatTRsplayaroleinpsychiatricdisease.TRsare one of the largest sources of genetic variation, are weakly tagged by SNPs, and play a significant role in regulatinggeneexpressionandsplicing.Intriguingly,>30MendeliandisordersarecausedbyTRexpansions. Nearly all repeat disorders involve neurological phenotypes, many have psychiatric components, and some implicatedgeneshavealsobeenidentifiedinschizophreniaGWAS. I hypothesize that tandem repeats play a significant role in schizophrenia risk and drive a subset of GWASsignals.IproposetodevelopanarrayofcomputationaltechniquestointegrateTRsintopsychiatricand other GWAS. In Aim 1 we will develop algorithms to accurately genotype long TR polymorphisms in large nextgenerationsequencingcohorts.InAim2wewillgenerateahighqualityreferencehaplotypepanelfora targetedsetofTRsusingtraditionalfamilybasedphasingmethodscombinedwithlongrangephasingfrom novelsinglemoleculesequencingtechnologies.InAim3wewilldeeplycharacterizemedicallyrelevantTRsin psychiatricdiseasebyimputingTRsintolargeexistingGWAScohorts.Finally,inAim4wewilldevelopanovel haplotypetestcapturinggenomewideTRassociationsfromexistingGWASdatasets.Takentogether,these innovations will provide a powerful framework for interrogating the role of TRs in human disease. Genomewide scans for association (Aim 4) can be combined with targeted methods of Aims 13 for genotyping or imputing TRs, fine mapping against other variant types, and performing functional follow up. Technologies for high throughput TR genotyping and imputation will revolutionize our ability to discover diseaseassociated TRs and enable unprecedented study of TRs in broad applications including GWAS, Mendeliangenetics,andcancer.